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tRNA METHYLTRANSFERASE 1; TRMT1

tRNA METHYLTRANSFERASE 1; TRMT1

Alternative titles; symbolstRNA METHYLTRANSFERASE 1, S. CEREVISIAE, HOMOLOG OFTRM1N2,N2-DIMETHYLGUANOSINE-26 tRNA METHYLTRANSFERASEtRNA(m(2,2)G26)DIMETHYLTRANSFE...

Alternative titles; symbols

  • tRNA METHYLTRANSFERASE 1, S. CEREVISIAE, HOMOLOG OF
  • TRM1
  • N2,N2-DIMETHYLGUANOSINE-26 tRNA METHYLTRANSFERASE
  • tRNA(m(2,2)G26)DIMETHYLTRANSFERASE

HGNC Approved Gene Symbol: TRMT1

Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:13,104,906-13,116,739 (from NCBI)

▼ Description
The TRMT1 gene encodes tRNA methyltransferase-1, which catalyzes dimethylation at the exocyclic 2-amino group of guanine 26 in tRNAs using S-adenosyl-L-methionine as substrate (Liu and Straby, 2000).

▼ Cloning and Expression
Liu and Straby (2000) identified human tRNA N2,N2-dimethylguanosine (m2,2G) dimethyltransferase (EC 2.1.1.32), which they called TRM1, by database searching with related sequences from yeast and C. elegans. The human cDNA encodes a deduced 659-amino acid protein that is 26% and 31% identical to the yeast and C. elegans homologs, respectively. When the human protein was expressed in E. coli, which lacks tRNA(m2,2G)dimethyltransferase activity, it was able to catalyze the formation of dimethylguanosine. Further, TRM1 specifically targeted the G26 position of human tRNA(Tyr). Mutation analysis showed that alterations in the conserved regions of the protein completely abrogated enzyme activity.

▼ Mapping
Scott (2007) mapped the TRMT1 gene to chromosome 19p13.3 based on an alignment of the TRMT1 sequence (GenBank BC040126) with the genomic sequence (build 36.2).

▼ Molecular Genetics
In affected members of a consanguineous Iranian family (M300) with autosomal recessive impaired intellectual development-68 (MRT68; 618302), Najmabadi et al. (2011) identified a homozygous frameshift mutation in the TRMT1 gene (611669.0001). The family was part of a large cohort of 136 consanguineous families with intellectual disability who underwent genetic analysis. Functional studies of the variant were not performed.

In 3 adult brothers, born of consanguineous Iranian parents (family 9000114), with MRT68, Davarniya et al. (2015) identified a homozygous frameshift mutation in the TRMT1 gene (611669.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in 100 Iranian controls. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.

In 4 patients from 2 unrelated consanguineous Pakistani families with MRT68, Blaesius et al. (2018) identified homozygous loss of function mutations in the TRMT1 gene (611669.0001 and 611669.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 68
TRMT1, 32-BP DEL, NT657
In a boy, born of consanguineous Pakistani parents (family 1), with autosomal recessive intellectual developmental disorder-68 (MRT68; 618302), Blaesius et al. (2018) identified a homozygous 32-bp deletion (c.657_688del32, NM_017722) in exon 7 of the TRMT1 gene, predicted to result in a frameshift and premature termination (Gln219HisfsTer22) in the methyltransferase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Blaesius et al. (2018) stated that the same homozygous mutation had previously been identified by Najmabadi et al. (2011) in affected members of a consanguineous Iranian family (M300) with a similar phenotype. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in the deletion of highly conserved residues in the functional domain of the protein.

.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 68
TRMT1, IVS12DS, G-T, +1
In 3 sibs, born of consanguineous Pakistani parents (family 2) with autosomal recessive intellectual developmental disorder-68 (MRT68; 618302), Blaesius et al. (2018) identified a homozygous G-to-T transversion in intron 12 of the TRMT1 gene (c.1506+1G-T, NM_017722), which was predicted to result in aberrant splicing and a loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.

.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 68
TRMT1, 2-BP DEL, 1332GT
In 3 brothers, born of consanguineous Iranian parents (family 9000114), with autosomal recessive intellectual developmental disorder-68 (MRT68; 618302), Davarniya et al. (2015) identified a homozygous 2-bp deletion (c.1332_1333delGT, NM_001136035.2) in the TRMT1 gene, predicted to result in a frameshift and premature termination (Tyr445LeufsTer28). The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases. It was absent in 100 Iranian controls. Functional studies of the variant and studies of patient cells were not performed.

Tags: 19p13.13